ABSTRACT Technology to deliver ?on demand? molecules that bind targets or catalyze reactions of choice has been a goal of chemistry for 50 years. Even today, theory is inadequate to support de novo design of receptors having useful affinity or catalysts having useful turnover. Thus, many have sought to create those catalysts on a DNA or RNA (collectively, xNA), using the Darwinism to these biomolecules to evolve, under laboratory selection pressure, those aptamers and xNAzymes. Unfortunately, because xNA is built from only four building blocks that carry few functional groups, laboratory in vitro evolution (LIVE) has provided few practical success stories. Firebird scientists created (30 years ago) an innovative and profoundly disruptive approach to this: We changed the structure of xNA, to give it higher information density, less ambiguous folds, and moieties that confer the functional power of proteins. We now apply LIVE to artificially expanded genetic information systems (AEGIS) (Fig. 1), using chemical theory for ?coarse design? and laboratory Darwinism for ?fine tuning?; theory cannot do ?fine tuning? and Darwinism cannot do ?coarse design?. Commercialized, we have now delivered five AEGIS-LIVE products. These have supported our hypothesis: by increasing the information density and functional group diversity of xNA libraries, AEGIS libraries will deliver functional xNA molecules more robustly than standard libraries, and this improvement will allow aptamers created by AEGIS-LIVE to compete with antibodies, especially in prescribed niches, and to compete with all technologies to generate catalysts. Our progress has attracted the Department of Defense as our next customer. The DoD is contracting Firebird to use AEGIS-LIVE to create aptamers to bind and detect antibiotics in blood samples to personalize treatment of patients being administered these drugs. This is an example of one of our two overlapping business models: (a) A custom research and/or collaboration model, where Firebird provides AEGIS-LIVE as a fee for service to generate receptors, ligands, and catalysts chosen by customers and clients. (b) A product generation model, where Firebird uses AEGIS-LIVE to generate receptors, ligands, and catalysts of its own choosing, as commercial products in their own right. This Phase 2 project will develop more case studies to illustrate the intrinsic advantages of AEGIS-LIVE aptamers over antibodies, and to provide counter-examples to the view that no matter how many more building blocks or functional groups AEGIS has, AEGIS aptamers can never gain any significant share of the ~$80 billion market enjoyed by antibodies, or be used in vivo. In addition to generating more aptamers, building signaling moieties on to them, and benchmarking their performance in blood and other biological fluids, the academic-commercial team joining Scripps, FfAME, and Firebird will expand AEGIS-LIVE to create catalysts on demand, specifically, sequence specific proteases, long a ?holy grail? for catalyst designers. These too will be tested in biological fluids to determine their limits in environments with many other proteins.